1. Field of the Invention
This invention relates to a novel class of peptidyl derivatives of aromatic diesters of .alpha.-aminoalkylphosphonic acids useful for selectively inhibiting elastase, selectively inhibiting chymotrypsin-like enzymes, selectively inhibiting trypsin-like enzymes and selectively inhibiting dipeptidyl peptidase IV (DPP-IV). The diesters of .alpha.-aminoalkylphosphonic acids are analogues of natural .alpha.-amino acids. This invention also relates to a method for controlling tumor invasion, treating inflammation and controlling blood coagulation in patients using the novel compounds of the present invention. We have found that peptidyl derivatives of aromatic diesters of .alpha.-aminoalkylphosphonic acids are potent inhibitors of chymotrypsin-like enzymes, elastases, blood coagulation enzymes, tryptases, kallikreins, and therefore they are useful as anti-tumor, anti-inflammatory and anticoagulant agents. We have also found that dipeptide proline phosphonates are inhibitors of dipeptidyl peptidase IV (DPP-IV, enzyme number EC 3.4.14.5, also known as CD26) and are thus useful in treatment of immune system disorders and acute respiratory distress syndrome (AIDS).
2. Description of the Related Art
Serine proteases play critical roles in several physiological processes such as digestion, blood coagulation, complement activation, fibrinolysis, and reproduction. Serine proteases are not only a physiological necessity, but also a potential hazard if they are not controlled. Blood coagulation serine proteases are responsible for vascular clotting, cerebral infarction and coronary infarction. Chymotrypsin-like enzymes and plasmin are involved in tumor invasion, tissue remodeling, and clot dissociation. Uncontrolled proteolysis by other serine proteases such as elastase may cause pancreatitis, emphysema, rheumatoid arthritis, inflammation and adult respiratory distress syndrome. Accordingly, specific and selective inhibitors of these proteases should be potent anticoagulants, anti-inflammatory agents and anti-tumor agents useful in the treatment of protease-related diseases. In vitro proteolysis by trypsin, chymotrypsin or the elastase family is a serious problem in the production, purification, isolation, transport or storage of peptides and proteins.
Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5, CD26) is a post-proline cleaving enzyme which will remove the dipeptides AA-Pro (AA=amino acid residue) from the N-terminus of proteins or polypeptides. DPP-IV has been found in a variety of mammalian cells and tissues including kidney, placenta, blood plasma and on the surface of certain T-lymphocyte subsets. Despite extensive studies, the biological role of DPP-IV in mammalian systems has not been completely established, although a number of functions have been postulated. DPP-IV may participate in the metabolism and uptake of proline-containing peptides in the intestine and kidney and may be involved in fibronectin-mediated cell movement and adhesion. DPP-IV may also play a role in the metabolism or catabolism of collagen which has a high frequency of Gly-Pro sequences. DPP-IV in human plasma has been shown to cleave N-terminal Tyr-Ala from growth hormone-releasing factor and cause inactivation of this hormone. DPP-IV is also involved in T-cell activation and regulation of T-cell proliferation. Thus, inhibitors of DPP-IV may have therapeutic utility in the modulation of the rejection of transplanted tissue by the host organism. Recently DPP-IV or CD26 has been postulated to act as a cofactor for entry into HIV in CD4.sup.+ cells (Callebaut, C., Krust, B., Jacotot, E., Hovanessian, A. G. T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4.sup.+ cells. Science. 1993, 262, 2045-2050). Thus inhibitors of DPP-IV should have therapeutic utility in the treatment of AIDS.